2-tertiaryamino or pyridyl alkyl-4,6 diphenyl-3 pyridazones

ABSTRACT

The new diphenyl-pyridazones are 4,6-di-(phenyl or substituted phenyl)-pyridaz-3-ones substituted at 2-position by a dialkylaminoalkyl group or an alkyl group substituted with a heterocycle containing a nitrogen atom. They are useful as psychotropic and analgesic drugs.

United States Patent [72] Inventor [21] Appl. No. [22] Filed [45] Patented [73] Assignee Seperic [32] Priority May 19, 1967 [33] Great Britain [31] 23,462/67 Jacques Baetz La Garenne-Colombes, France 726,749

May 6, 1968 Nov. 23, 197 1 s41 Z-TERTIARYAMINO 0R PYRIDYL ALKYL-4,6

DlPHENYL-S PYRIDAZONES 6 Claims, 2 Drawing Figs.

[52] U.S.fl 260/247.l,

[51] Int. Cl C07d 87/46 [50] Field of Search 260/250, 247.2, 247.1

[56] References Cited UNITED STATES PATENTS 2,783,232 2/1957 Gutmann et a1. 260/250 3,017,411 1/1962 Enge1brecht et al. 260/2472 Primary Examiner-Nicholas S. Rizzo Assistant Examiner-Jose Tovar Attorney-Young & Thompson ABSTRACT: The new diphe'nyl-pyridazones are 4,6-di-( pheny1 or substituted phenyl)pyridaz-3-ones substituted at 2-position by a dialkylaminoalkyl group or an alkyl group substituted with a heterocycle containing a nitrogen atom. They are useful as psychotropic and analgesic drugs.

Z-TERTIARYAMI NO OR PYRIDYL ALKYL-4,6 DIPHENYL-3 PYRIDAZONFS The present invention relates to a family of new chemical compounds having therapeutic properties. These compounds are those of general formula (I), illustrated in FIG. 1 of the accompanying drawing, wherein Ar and Ar, which may be the same or difi'erent, are phenyl groups, or phenyl groups monoor poly-substituted with halogen atoms, alkyl, hydroxy, alkoxy, alkylamino or trifluoromethyl groups, X is hydrogen or lower alkyl, n is an integer equal to l or more, the various Xs, when n is greater than 1, not being necessarily identical, and Y is a dialkylamino group or a heterocycle containing a nitrogen atom, alkyl-substituted or not, said heterocycle eventually comprising a second heteroatom and being bound to group (CH X), by its nitrogen atom or one of its nuclear carbons, and their acid addition salts, particularly with pharmaceutically acceptable avids.

Thus, compounds (I) are 2-substituted 4,6-diphenylpyridaz- 3-ones.

Compounds (I) have a psychotropic and analgesic activity.

The presence, at 4-position, of a substituted or unsubstituted benzene nucleus imparts to such compounds a particularly marked activity.

In the aforesaid definition of compounds (I), the alkyl groups and the alkyl moieties of the alkoxy, alkylamino and dialkylamino groups are advantageously lower alkyls, particularly of one to four carbon atoms.

Similarly, n is preferably an integer of 1-3.

Finally, when Ar is a substituted phenyl group, meta substitution is preferred.

To prepare such compounds, there is used a process the main steps of which are illustrated in FIG. 2 of the accompanying drawing.

This process uses, as starting materials, a;y-diphenyl-'yketonic acids (VI). Compounds (VI) are generally known, the preparation thereof being described and illustrated in the drawing only for information purposes. For such preparation, the starting materials are acetophenones (II) which are condensed (stage a) with benzaldehydes (III) at room temperature, in the presence of sodium hydroxide or other alkaline base, in ethanol or some other suitable solvent. After washing and drying, the resulting benmlacetophenones (IV) are treated (stage b) with potassium cyanide in the presence of acetic acid. The resulting nitriles (V) are washed and dried, and are then hydrolyzed with refluxing sodium hydroxide during several hours (stage c), and acids (VI) are then precipitated with hydrochloric acid, and are then washed and dried.

Starting from the resulting a;y-diphenyl-y-ketonic acids (VI), the process according to the invention comprises condensing such acids, or an ester of such acids, with hydrazines of general formula H NNHR, wherein R is hydrogen or a (CHX ),,Y group wherein X, Y and n have the same meaning as in formula (I) above, thus obtaining 4,6-diphenylpyridazinones of formula:

dehydrogenating such pyridazinones to the corresponding pyridazones and, when R is hydrogen, introducing group (CHX ),,-Y by condensation of the 2-unsubstituted diphenylpyridazone with a halide of formula Z(CHX),,-V, wherein Z is halogen.

The various stages of the process will now be examined in greater detail with reference to FIG. 2. In the FIG., for purposes of clarity, the case where, in hydrazines H,NNHR, R is hydrogen is distinguished from the case where R is (Cl-IX),,Y.

Thus, the condensation of a,'y-diphenyl-'y-ketonic acids (VI) with substituted hydrazines constitutes stage d, whereas condensation with the unsubstituted hydrazine constitutes stage d,.

Condensation with hydrazines according to stages d or d, is carried out in a suitable solvent, such as butanol. which, owing to the formation of an azeotrope, makes it possible to remove the two molecules of water resulting from the condensation. It should be noted that such condensation may be carried out just as readily with the a,'y-diphenyl-y-ketonic acids (VI) in the form of simple esters (such as methyl, ethyl, etc.)

Thus, depending on whether route d or d is used, there are produced pyridazinones (VII or (VII bis).

Such pyridazinones (Vll) or (Vll bis) are then dehydrogenated at 4,5-position with bromine in acetic acid, thus giving Z-substituted 4,6-diphenyl-pyridaz-3-ones (1), according to route e, or 2-unsubstitutcd 4,6-diphenyl-pyridaz-3- ones (VIII) according to route e,. The Z-unsubstituted pyridazones (VIII) are condensed (stage f) with halides of general formula Z-(CHX),,Y, wherein Y and 2 have the same meaning as above. The condensation may be carried out in the presence of an alkali metal alkoxide such as sodium methoxide or ethoxide, within the corresponding alcohol. As a modification, this condensation may be effected within water, in the presence of an alkaline base, such as sodium hydroxide. In addition, it should be noted that the order of stages e and f may be reversed. This amounts to effecting the preparation according to stages d and e, stage d being merely divided into two successive condensations, the first with hydrazine NH,- NH,, and the second with halide Z(CHX),,Y.

Pyridazones (I), of basic character, may be converted into suitable salts of inorganic acids, such as the hydrochlorides, or salts of organic acids, such as the methane-sulfonates, to facilitate their use.

Conjugation with an acid may be obtained at an earlier stage, for example at the stage where dehydrogenation of the pyridazinones is effected, in which case, the desired salt will be obtained directly (see examples 3 and 4, below).

In addition to compounds (I), compounds (VII), (VII bis) and (VIII) are new compounds.

The examples below are given to illustrate the invention. There are described only the stages starting from compounds (VI EXAMPLE I Z-(B-morpholino-ethyl)-4-(o-chlorophenyl)-6-phenylpyridaz-S-one (Code Number; 450) (Compound I, Ar o-chlorophenyl, Ar phenyl, (CI-IX),,=CH CH Y morpholino) Stage d In a 250 ml. flask, introduce 29.4 g. of (o-chlorophenyU-B- benzoyl-propionic acid (VI) and 60 ml. of butanol. Warm to dissolve and add a solution of 15.5 g. of morpholino-ethylhydrazine in 31 ml. of butanol. Heat to reflux temperature, and distill slowly the binary butanol/water azeotrope. Terminate the operation when pure butanol is collected. Bring to dryness, under vacuum of the water-pump. The resulting yellow oil is dissolved in 500 ml. of chlorofonn, treated with gaseous hydrochloric acid, and is then filtered and washed with ethanol-water. The chloroform phase is dried over dry sodium sulfate and the solution is brought to dryness, in vacuo, to give friable froths used as such in the following stage.

Stage In a 1 liter flask, dissolve 44 g. of 2-(B-morpholino-ethyl)-4- (o-chlorophenyl)-6-phenylpyridazinone hydrochloride (compound (VII formed by the friable froths from stage d above) in 660 ml. of acetic acid. The resulting light yellow solution is heated at 70 C. and a solution of 16.3 g. of bromine in 81.5 ml. of acetic acid is cautiously introduced therein. Heat to refluxing during 2 hours. The resulting hydrobromic acid is evolved and the solution becomes dark red. After drying, the resulting brown oil is dissolved in 750 ml. of chloroform to which are added, with vigorous stirring, 280 ml. of 2N sodium hydroxide: the oil dissolves in the chloroform when the pH becomes alkaline. After washing and drying, add 200 ml. of ethanol, and then remove the remaining ethanol by distillationLCrystallization is obtained by scratching, and the material is left overnight in the ice-chest. The crystals are suction filtered, washed with ice-cold ethanol, and are then dried in vacuo overnight in the presence of potassium hydroxide.

After recrystallization from methanol, 28.2 g. of pink colored Z-(fl-morpholino-ethyl) -4-(o-chlorophenyl)-6-phenyl-piridaz-3-one are obtained.

Melting point: 127 C.

EXAMPLE 2 2-(B-morpholino-ethyl)-4-( m-chlorophenyl)-6-phenylpyridaz-3-one (Code Number: 390).

(Compound I, Ar= m-chlorophenyl, Ar phenyl, (CHX),,=CH,CH,, Y morpholino).

Stage d 26.9 g. of a-m-chlorophenyl-y-phenyl-'y=-ketobutyric acid (Vl) are dissolved in 60 ml. of hot butanol. 14.5 g. of B- morphollneoethyl-hydrazlne dlssolved in 40 ml. of butanol are ric acid. The material is washed with an ethanol-water mixture and is then dried in vacuo. g. of 2-(Bmorpholinoethyl)-4- (m-chlorophenyl)-6-phenyl-pyridazin-3-one hydrochloride (compound Vll, Ar m-chlorophenyl, Ar phenyl, (Cl-1X ),,=CH,-CH,-, Y morpholino) are thus obtained.

Stage e The pyridazinone (39 g.) obtained in stage d above is dissolved in 530 ml. of pure acetic acid and, after heating at 60 C., a solution of 15.5 g. of bromine in 80 ml. of acetic acid is slowly added thereto, with stirring. The mixture is refluxed during 2.5 hours. The red colored solution is dried in vacuo. The resulting reddish oil is taken up into 850 ml. of chloroform, and 2N sodium hydroxide is added thereto to alkaline pH. The material is decanted, washed with water, dried over sodium sulfate, washed with chloroform and is then brought to dryness in vacuo. The resulting oil, dissolved in 140 ml. of ethanol, crystallizes on scratching. After suction filtering and washing with cold ethanol, there are obtained 30 g. of crude product which is recrystallized by treatment with 250 ml. of refluxing ethanol, and is filtered hot: the product crystallizes on cooling. After resting overnight in the ice-chest, the product is suction filtered, washed with cold ethanol, and is then dried in vacuo in the presence of potassium hydroxide. 28 g. of Z-(B-morpholino-ethyl)-4-(rn-chlorophenyl)-6-phenyl-pyridaz-3-one are thus obtained.

Melting point =1 18 C.

To prepare the hydrochloride, 16.9 g. of this base are dissolved in 100 ml. of hot acetone. Gaseous hydrochloric acid is bubbled through it. The hydrochloride crystallizes on cooling. This is washed with 1X20 ml. of acetone and then with 2X15 ml. of ether. After drying in vacuo at room temperature during 3 hours, 18.3 g. of 2(B-morpholino-ethyl)-4-(m-chlorophenyl)-6-phenyl-pyridaz-3-one, m.p. 222223 C., are obtained.

EXAMPLE 3 Ar phenyl,

Stage d,

In a 500 ml. flask, 29 g. of a-(m-chlorophenyh- -y-phenyl-'yketobutyric acid (VI) are dissolved in 140 ml. of butanol. 5.5 g. of hydrazine hydrate are gradually added. The water formed is removed by distillation of 30 ml. of the butanol/water azeotrope. The remaining butanol solution is filtered hot. Crystallization is instantaneous. After 1 hour, the material is suction filtered, washed with butanol and ethanol, and is then dried in the presence of potassium hydroxide. There are thus obtained 23.9 g. of 4-(m-chlorophenyl)-6-phenyl-pyridazin-3- one (Compound (Vll bis), Ar m-chlorophenyl, Ar phenyl).

Stage a,

14.5 g. of the pyridazinone obtained in stage d above are dissolved in 400 ml. of acetic acid, at 50-55 C., and 3.9 ml. of bromine diluted in 35 m1. of acetic acid are added thereto over 45 minutes. After heating at C. during 1 hour, the hydrobromic fumes are removed. The cooled solution is evaporated to dryness. The residue is taken up into ml. of methanol and crystals appear. The material is suction filtered and washed with methanol. After drying, there are obtained 15.2 g. of brominated material which is refluxed during 1 hour in 100 ml. of acetic acid with 3.7 g. of dry sodium acetate. Crystallization occurs on cooling. There are thus obtained 1 1.8 g. of 4-(m-chlorophenyl)-4-phenyl-pyridaz-3-one (Compound Vlll, Ar m-chlorophenyl, Ar phenyl Stage f Nine g. of the pyridazone obtained in stage e above are added to 100 ml. of alcohol with 24 ml. of sodium ethoxide solution formed by adding 3 g. of sodium to a sufi'rcient amount of ethanol to give 100 ml. The sodium derivative dissolves in the cold: this is solution A. On the other hand, 5.25 g. of w-4-chloropicoline hydrochloride are converted into the base by addition of 24.5 ml. of the same sodium ethoxide solution: this is solution B. Solutions A and B are combined and are refluxed during 1 hour and 45 minutes. The material is then suction filtered and concentrated to dryness. This is taken up into 50 m1. of methanol and methane-sulfonic acid is added to acidic pH. The crystalline methane-sulfonate is then precipitated with the just sufficient amount of isopropyl ether. This is then suction filtered and dried in a desiccator. There are thus obtained 10 g. of 2-(y-picolyl)-4-(m-chlorophenyl)- 6-phenyl-pyridaz-3-one methane-sulfonate.

The melting point of said methane sulfonate is 202 C.

EXAMPLE 4 Z-(B-morpholino-ethyl)-4,6-di-(p-methoxphenyl)-pyridaz-3- one (Compound 1, Ar Ar p-methoxyphenyl, (CHX),,= CH,CH,, Y morpholino).

Stage d 15.7 g. of a, 'y-di-(p-methoxyphenyl)--y-ketobutyric acid (VI) are dissolved in 70 ml. of hot butanol. There are slowly added thereto 7.25 g. of B-morpholino-ethyl-hydrazine dis- Stage e 9.2 g. of the pyridazinone obtained in stage d above are dissolved in ml. of acetic acid, with stirring and while Code No.

Empirical formula Melting point, C.

TABLE.DIPHENYL-PYRIDAZONES OF FORMULA (I)-CODl;inued (CI IX) Y As indicated previously, compounds l) have a pyschotropic and analgesic activity that was demonstrated by means of the main pharmacological tests described below:

l-Measure of the inhibition of the number of twisting movements produced in mice on intraperitoneal injection of 0.25 ml. per mouse of a phenylbenzoquinone solution containing 25 mg. of phenylbenzoquinone per ml.

The test compounds are administered to the animals 10 minutes prior to the phenylbenzoquinone injection and the twisting movements are counted during 1 hour for each animal.

Generally, injection of phenylbenzoquinone alone causes fifty twisting movements per hour; were considered as being particularly active those compounds that inhibited such twisting movements by more than 70 percent, at a dosage equivalent to one-fifth of the LD 50: (the compounds are listed under their Code No):

2--Measure of the reaction time of mice to immersion of the tail of the animals in water heated to a temperature of 58 C.

When no product has been administered to the animal, the animal moves its tail within 1% seconds.

The test compounds are administered to the animal 15 minutes prior to the first immersion: immersion of the tail is effected every 30 minutes during 2.5 hours.

Were considered as particularly active those compounds that extended by 3-4 seconds the reaction time of the animal, at a dosage equivalent to one-filth the LD 50:

3Measure of the reaction time of mice placed over a plate maintained at a constant temperature of 56 C.; generally, the mice manifest pain to heat by paw-licking and agitation, after 10 to 20 seconds.

Were considered particularly active those compounds that extended by 10 to 15 seconds this reaction time:

4Study of the behavior of mice and rats under the influence of a dosage equivalent to one-fifth of the LD 50 of the test compounds. This behavior being evaluated with respect to systemic sedation with decubitus, sleep, catatonic or cataleptic attitudes.

Were found particularly active the products listed under Code Numbers:

has been isolated, or of another male mouse maintained in normal conditions.

Were considered as particularly active those compounds that inhibited completely this aggressivity during 2 hours, at a dosage representing one-fortieth of LD 50: 445-499- Q. 1.5- i.

These sedative and analgesic properties are also found to occur in Humans and are thus applicable in human clinics, compounds (I) being administrable by the oral, parenteral or rectal route, at a daily dosage regimen of 100 mc. to 2 g.; the injectable route will be more particularly reserved for the water-soluble compounds, although it is possible to inject water-insoluble compounds by using another solvent.

For such administrations, the compounds are formulated as therapeutic compositions with the vehicles or excipients suitable for these various routes of administration. The compositions formulated in unit dosage form such as tablets, suppositories, ampoules, contain preferably from 100 to 400 mg. of compound (I).

Examples of suitable formulations are given below purely for illustrative purposes:

A. Formulation for ampoules:

Compound n 39] 100 mg. Sterile pyrogen-free water, q.a. to make 5 ml. B. Formulation for one tablet:

Compound n 390 200 mg. Lactose Starch )q.s. for one tablet finished at 400 mg. Talc C. Formulation for one suppository:

Compound n 445 200 mg.

Semisynthetic glycerine. q.s. for one suppository weighing 2.5 g.

Having now described my invention what I claim as new and desire to secure by letters patent is:

l. A compound selected from the group consisting of compounds of the formula:

wherein:

Ar and Ar are each selected from the group consisting of phenyl and mono-substituted phenyl selected from the group consisting of halophenyl, alkylphenyl having one-four carbon atoms in the alkyl group, hydroxyphenyl, alkoxyphenyl haVing one-four carbon atoms in the alkoxy group, alkylaminophenyl having one-four carbon atoms in the alkyl group and trifluoromethylphenyl,

Y is selected from the group consisting of di-lower alkylamino, morpholino, pyridyl, pyrrolidino, piperidino and N-alkyl-piperazino having one-four carbon atoms in the alkyl group,

n is an integer from I to 3 but n is l when Y is pyridyl,

and the acid addition salts thereof.

2. Z-(B-morpholino-ethyl)-4-phenyl-6-(m-chlorophenyl)- pyridaz-3-one or its salts.

3. Z-(B-pyrrolidino-ethyl)-4-phenyl-6-(m-chlorophenyl)- pyridaz-3-one or its salts.

4. Z-(B-piperidino-ethyl)-4-phenyl-6-(m-chlorophenyl)- pyridaz-3-one or its salts.

methylphenyl)-pyridaz-3-one or its salts.

6. 2-(B-pyrrolidino-ethyl )-4-phenyl-6-( m-trifluo romethylphenyl)-pyridaz-3-one or its salts.

* I. l k 

2. 2-( Beta -morpHolino-ethyl)-4-phenyl-6-(m-chlorophenyl)-pyridaz-3-one or its salts.
 3. 2-( Beta -pyrrolidino-ethyl)-4-phenyl-6-(m-chlorophenyl)-pyridaz-3-one or its salts.
 4. 2-( Beta -piperidino-ethyl)-4-phenyl-6-(m-chlorophenyl)-pyridaz-3-one or its salts.
 5. 2-( Beta -piperidino-ethyl)-4-phenyl-6-(m-trifluoro-methylphenyl)-pyridaz-3-one or its salts.
 6. 2-( Beta -pyrrolidino-ethyl)-4-phenyl-6-(m-trifluoro-methylphenyl)-pyridaz-3-one or its salts. 